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Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression

Mario Pescatori^*,,1, Aldobrando Broccolini^*, Carlo Minetti, Enrico Bertini, Claudio Bruno, Adele D’amico, Camilla Bernardini, Massimiliano Mirabella^*,, Gabriella Silvestri^*, Vincenzo Giglio^||,, Anna Modoni^*, Marina Pedemonte, Giorgio Tasca^*, Giuliana Galluzzi, Eugenio Mercuri^*, Pietro A. Tonali^*, and Enzo Ricci^*,,1

^* Institute of Neurology, Catholic University, Rome, Italy;

Neuromuscular Disease Unit, Department of Pediatrics, G. Gaslini Institute, University of Genova, Genova, Italy;

Unit of Molecular Medicine and Pathology, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy;

Institute of Anatomy and Cell Biology, Catholic University, Rome, Italy;

^|| Division of Cardiology and ICU, St. Paolo Hospital, Civitavecchia, Italy;

Center for Neuromuscular Diseases, UILDM, Rome, Italy; and

Don Gnocchi Foundation, ONLUS, Rome, Italy

¹Correspondence: M.P. and E.R.: Institute of Neurology, Catholic University, L.go A. Gemelli 8, 0018, Rome, Italy. E-mail: m.pescatori{at}rm.unicatt.it; ericci{at}rm.unicatt.it

Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) patients has been used to describe muscle tissue alterations in DMD children older than 5 years. By studying the expression profile of 19 patients younger than 2 years, we describe with high resolution the gene expression signature that characterizes DMD muscle during the initial or "presymptomatic" phase of the disease. We show that in the first 2 years of the disease, DMD muscle is already set to express a distinctive gene expression pattern considerably different from the one expressed by normal, age-matched muscle. This "dystrophic" molecular signature is characterized by a coordinate induction of genes involved in the inflammatory response, extracellular matrix (ECM) remodeling and muscle regeneration, and the reduced transcription of those involved in energy metabolism. Despite the lower degree of muscle dysfunction experienced, our younger patients showed abnormal expression of most of the genes reported as differentially expressed in more advanced stages of the disease. By analyzing our patients as a time series, we provide evidence that some genes, including members of three pathways involved in morphogenetic signaling—Wnt, Notch, and BMP—are progressively induced or repressed in the natural history of DMD.—Pescatori, M., Broccolini, A., Minetti, C., Bertini, E., Bruno, C., D’amico, A., Bernardini, C., Mirabella, M., Silvestri, G., Giglio, V., Modoni, A., Pedemonte, M., Tasca, G., Galluzzi, G., Mercuri, E., Tonali, P. A., Ricci, E. Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression.

Key Words: microarrays • Duchenne muscular dystrophy • human disease • Wnt, Notch, and BMP signaling

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